Viral infections are a major threat to human health and account for many serious infectious diseases. Hepatitis C virus (HCV), a major cause of viral hepatitis, has infected more than 200 million people worldwide. Current treatment for HCV infection is restricted to immunotherapy with interferon-α alone or in combination with ribavirin, a nucleoside analog. This treatment is effective in only about half the patient population. Therefore, there is an urgent need for new HCV drugs. Hepatitis C virus comprises a positive-strand RNA genome enclosed in a nucleocapsid and lipid envelope and consists of approximately 9600 ribonucleotides, which encodes a polyprotein of about 3000 amino acids (Dymock et al. Antiviral Chemistry & Chemotherapy 2000, 11, 79). A HCV protein, NS5B, released from the polyprotein, possesses polymerase activity and is involved in the synthesis of double-stranded RNA from the single-stranded viral RNA genome that serves as the template. The reproduction of HCV virus may be prevented through the manipulation of NS5B's polymerase activity. The competitive inhibition of NS5B protein would suppress or prevent the formation of the double-stranded HCV RNA. Alternatively, a nucleoside analog also may be incorporated into the extending RNA strand and act as a chain-terminator. Furthermore, a deteriorating nucleoside analog also may be incorporated into the extending RNA, which may cause mutagenic damage to the viral genome. Recently, several PCT patent applications (WO 99/43691, WO 01/32153, WO 01/60315, WO 01/79246, WO 01/90121, WO 01/92282, WO 02/18404, WO 02/057287, WO 02/057425) have described nucleoside analogs as anti-HCV agents in in vitro assays.
Hepatitis B virus (HBV) has acutely infected almost a third of the world's human population, and about 5% of the infected are chronic carriers of the virus (Delaney IV et al. Antiviral Chemistry & Chemotherapy 2001, 12, 1-35). Chronic HBV infection causes liver damage that frequently progresses to cirrhosis and/or liver cancer later in the life. Despite the availability and widespread use of effective vaccines and chemotherapy, the number of chronic carriers approaches 400 million worldwide. Therefore, more effective anti-HBV drugs need to be developed. Human immunodeficiency virus (HIV) causes progressive degeneration of the immune system, leading to the development of AIDS. A number of drugs have been used clinically, including reverse transcriptase inhibitors and protease inhibitors. Currently, combination therapies are used widely for the treatment of AIDS in order to reduce the drug resistance. Despite the progress in the development of anti-HIV drugs, AIDS is still one of the leading epidemic diseases. Certain acute viral infections also impose a great threat to human life, including the newly-discovered West Nile virus and SARS virus.
Bacterial infections long have been the sources of many infectious diseases. The widespread use of antibiotics produces many new strains of life-threatening bacteria Fungal infections are another type of infectious diseases, some of which also can be life-threatening. There is an increasing demand for the treatment of bacterial and fungal infections. Antimicrobial drugs based on new mechanisms of action are especially important.
Proliferative disorders are one of the major life-threatening diseases and have been intensively investigated for decades. Cancer now is the second leading cause of death in the United States, and over 500,000 people die annually from this proliferative disorder. All of the various cells types of the body can be transformed into benign or malignant tumor cells. Transformation of normal cells into cancer cells is a complex process and thus far is not fully understood. The treatment of cancer consists of surgery, radiation, and chemotherapy. While chemotherapy can be used to treat all types of cancer, surgery and radiation therapy are limited to certain cancer at certain sites of the body. There are a number of anticancer drugs widely used clinically. Among them are alkylating agent such as cisplatin, antimetabolites, such as 5-fluorouracil, and gemcitabine. Although surgery, radiation, and chemotherapies are available to treat cancer patients, there is no cure for cancer at the present time. Cancer research is still one of the most important tasks in medical and pharmaceutical organizations.
Nucleoside drugs have been used clinically for the treatment of viral infections and proliferative disorders for decades. Most of the nucleoside drugs are classified as antimetabolites. After they enter cells, nucleoside analogs are phosphorylated successively to nucleoside 5′-monophosphates, 5′-diphosphates, and 5′-triphosphates. In most cases, nucleoside triphosphates, e.g., 3′-azido-3′-deoxythymidine (AZT, an anti-HIV drug) triphosphate and arabinosylcytosine (cytarabine, an anticancer drug) triphosphate, are the active chemical entities that inhibit DNA or RNA synthesis, through a competitive inhibition of polymerases and subsequent incorporation of modified nucleotides into DNA or RNA sequences. In a few cases, nucleoside analogs exert effects at lower phosphate levels. For instance, 5-fluoro-2′-deoxyuridine (an anticancer drug) 5′-monophosphate and 2′,2′-difluoro-2′-deoxycytidine (an anticancer drug) 5′-diphosphate have been shown to inhibit thymidylate synthase and ribonucleotide reductase, respectively. Although nucleoside analogs themselves may act at the nonphosphate level such as the inhibitors of adenosine kinases and the ligands of adenosine receptors, currently, clinically-useful nucleoside drugs primarily depend on cellular activation by nucleoside kinases and nucleotide kinases.
At least, two criteria are pertinent for nucleoside antiviral drugs: 1. nucleoside analogs should anabolize to nucleotides in cells; and 2. the anabolized nucleotides should target selectively viral enzymes. In order to be phosphorylated in cells and selectively to target preferred enzymes, nucleoside analogs should have favorable modifications on their sugar and base moieties. To obtain such favorable nucleoside analogs, a general approach is to generate diverse nucleoside analogs by modifying the base or the sugar, or by modifying both base and sugar moieties. Numerous examples exist in the literature for the synthesis of a variety of modified nucleosides (Chemistry of Nucleosides and Nucleotides Vol. 1 (1988), Vol. 2 (1991), Vol. 3 (1994), edited by Leroy B. Townsend, Plenum Press).
However, there are certain classes of nucleoside compounds that were not explored intensively for their antiviral and anti-proliferative activities before the present invention. A class of such compounds is tricyclic nucleosides. Disclosures on tricyclic nucleosides are very limited considering the existence of various tricyclic heterocycles. A well-known tricyclic nucleoside is triciribine (TCN), having potent cytotoxicity against cancer cells (Porcari et al. J. Med. Chem. 2000, 43, 2438-2448). A number of its modified derivatives were prepared and screened against viruses and cancer (Porcari et al. Nucleosides Nucleotides 1999, 18, 2475-2497; J. Med. Chem. 2000, 43, 2457-2463). Another known tricyclic nucleoside is 2-(2-deoxy-β-D-erythro-pentofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenz[cd]azulen-7-one, but its biological activity was not reported (Helv. Chim. Acta, 2000, 83, 911-927). The PCT publication WO 03/061385 describes tricyclic nucleoside libraries. The present invention discloses novel tricyclic nucleosides and nucleotides and their use for the treatment of infectious disease, including viral infections, and of proliferative disorders, including cancer.